Maddalena Mauri

This cross-sectional study aims to identify clusters of internalizing and externalizing traits during adolescence using a bottom-up approach. The second aim is to investigate whether the different clusters differ by environmental risk factors and specific epigenetic profiles. A total of 205 adolescents, who had been referred for psychopathology in childhood, were recruited. Behavioral problems were assessed using the Child Behavior Checklist/6–18 (CBCL). Different clusters of psychopathological profiles were analyzed using a Finite mixture model. Differences in environmental risk factors and epigenetic profiles were tested with χ²-tests and Bonferroni-corrected t-tests. Two clusters were identified: a LOW cluster (51% of the sample), characterized by the presence of subclinical mean scores in both internalizing and externalizing problems, and a HIGH cluster (49% of the sample), characterized by high mean scores in both domains. The HIGH cluster had a significantly greater number of perinatal complications and changes in methylation of specific CpG sites of Brain-derived neurotrophic factor, Insulin-like growth factor-2, and Oxytocin receptor, whereas no difference was found for FK506-binding protein 5. Our results confirm the existence of a strong association between early adverse events, DNA methylation, and the presence of behavioral problems and psychopathological traits in adolescence.

Although heritability estimates suggest a role for genetic components, environmental risk factors have been described as relevant in the etiology of attention deficit/hyperactivity disorder (ADHD). Several studies have investigated the role of toxicological pollution, i.e., air pollution, heavy metals, POPs, and phthalates. Clear evidence for association of ADHD and environmental factors has not been provided yet. To answer this, we have assessed all available systematic reviews and meta-analyses that focused on the association between pollutant exposure and either ADHD diagnosis or symptoms. More than 1800 studies were screened of which 14 found eligible. We found evidence of a significant role for some pollutants, in particular heavy metals and phthalates, in the increased risk of developing ADHD symptoms. However, at the current stage, data from existing literature also do not allow to weight the role of the different environmental pollutants. We also offer a critical examination of the reviews/meta-analyses and provide indications for future studies in this field. PROSPERO registration: CRD42022341496

The brain’s intrinsic organization into large-scale functional networks, the resting state networks (RSN), shows complex inter-individual variability, consolidated during development. Nevertheless, the role of gene and environment on developmental brain functional connectivity (FC) remains largely unknown. Twin design represents an optimal platform to shed light on these effects acting on RSN characteristics. In this study, we applied statistical twin methods to resting-state functional magnetic resonance imaging (rs-fMRI) scans from 50 young twin pairs (aged 10–30 years) to preliminarily explore developmental determinants of brain FC. Multi-scale FC features were extracted and tested for applicability of classical ACE and ADE twin designs. Epistatic genetic effects were also assessed. In our sample, genetic and environmental effects on the brain functional connections largely varied between brain regions and FC features, showing good consistency at multiple spatial scales. Although we found selective contributions of common environment on temporo-occipital connections and of genetics on frontotemporal connections, the unique environment showed a predominant effect on FC link- and node-level features. Despite the lack of accurate genetic modeling, our preliminary results showed complex relationships between genes, environment, and functional brain connections during development. A predominant role of the unique environment on multi-scale RSN characteristics was suggested, which needs replications on independent samples. Future investigations should especially focus on nonadditive genetic effects, which remain largely unexplored.

Individual responses to methylphenidate (MPH) can significantly differ in children with attention-deficit/hyperactivity disorder (ADHD) in terms of the extent of clinical amelioration, optimal dosage needed, possible side effects, and short- and long-term duration of the benefits. In the present repeated-measures observational study, we undertook a proof-of-concept study to determine whether clustering analysis could be useful to characterize different clusters of responses to MPH in children with ADHD. We recruited 33 children with ADHD who underwent a comprehensive clinical, cognitive, and neurophysiological assessment before and after one month of MPH treatment. Symptomatology changes were assessed by parents and clinicians. The neuropsychological measures used comprised pen-and-paper and computerized tasks. Functional near-infrared spectroscopy was used to measure cortical hemodynamic activation during an attentional task. We developed an unsupervised machine learning algorithm to characterize the possible clusters of responses to MPH in our multimodal data. A symptomatology improvement was observed for both clinical and neuropsychological measures. Our model identified distinct clusters of amelioration that were related to symptom severity and visual-attentional performances. The present findings provide preliminary evidence that clustering analysis can potentially be useful in identifying different responses to MPH in children with ADHD, highlighting the importance of a personalized medicine approach within the clinical framework.

This study aims to investigate the genetic and neural determinants of attention and hyperactivity problems. Using a proof-of-concept imaging genetics mediation design, we explore the relationship between the glutamatergic GRIN2B gene variants and inattention/hyperactivity with neuroanatomical measures as intermediates. Fifty-eight children and adolescents were evaluated for behavioral problems at three time points over approximately 7 years. The final assessment included blood drawing for genetic analyses and 3T magnetic resonance imaging. Attention/hyperactivity problems based on the Child Behavior Checklist/6-18, six GRIN2B polymorphisms and regional cortical thickness, and surface area and volume were estimated. Using general linear model (GLM) and mediation analyses, we tested whether GRIN2B exerted an influence on stable inattention/hyperactivity over development, and to what extent this effect was mediated by brain morphology. GLM results enlightened the relation between GRIN2B rs5796555-/A, volume in the left cingulate isthmus and inferior parietal cortices and inattention/hyperactivity. The mediation results showed that rs5796555-/A effect on inattention/hyperactivity was partially mediated by volume in the left isthmus of the cingulate cortex, suggesting a key role of this region in translating glutamatergic GRIN2B variations to attention/hyperactivity problems. This evidence can have important implications in the management of neurodevelopmental and psychiatric disorders.

Background: Increasing evidence suggests a complex role of family influences, such as the exposure to parent psychopathology through parenting behavior, in parent-to-child psychopathology transmission. Parenting behaviour could represent a relevant target of psychoeducative intervention. Given these premises, we aimed to evaluate homotypic and heterotypic relationships between parent and child psychopathology, mediated by parenting behaviours, taking into account the constructs of parent and offspring internalizing and externalizing psychopathology. Methods: Internalizing and externalizing symptoms in 272 clinically-referred subjects (mean age = 14.5 ± 2.3; F = 23.5%) and their parents (mothers n = 272, fathers n = 242) were assessed through the Child Behavior Checklist and the Adult Self Report; four areas of parenting behaviours were investigated through the Family Life Questionnaire. Multiple mediation models were built, considering mother and father psychopathology scales as independent variables, parenting measures and family functioning as mediators (Affirmation, Rules, Discipline and Special Allowances), child psychopathology scales as dependent variables and demographic variables as covariates. Results: Regression models showed a significant effect of maternal internalizing symptomatology on child externalizing behavioral problems; high levels of maternal pathology predicted high levels of children’s psychopathology. A total mediating effect of parenting measures was found: high levels of internalizing symptoms in mothers predicted low levels of affirmation, which in turn predicted high levels of externalizing psychopathology in children. Conclusions: Our study results confirmed the existence of interdependent links between mothers’ psychiatric symptomatology, parenting behaviour and offspring outcomes, specifically in an Italian context. On a clinical and rehabilitation basis, this work offers suggestions about parenting practices, specifically maternal, involved in the maintenance of child psychopathology.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents, with environmental and biological causal influences. Pharmacological medication is the first choice in ADHD treatment; recently, many studies have concentrated on dietary supplementation approaches to address nutritional deficiencies, to which part of non-responses to medications have been imputed. This review aims to evaluate the efficacy of non-pharmacological supplementations in children or adolescents with ADHD. We reviewed 42 randomized controlled trials comprised of the following supplementation categories: polyunsaturated fatty acids (PUFAs), peptides and amino acids derivatives, single micronutrients, micronutrients mix, plant extracts and herbal supplementations, and probiotics. The reviewed studies applied heterogeneous methodologies, thus making it arduous to depict a systematic overview. No clear effect on single cognitive, affective, or behavioral domain was found for any supplementation category. Studies on PUFAs and micronutrients found symptomatology improvements. Peptides and amino acids derivatives, plant extracts, herbal supplementation, and probiotics represent innovative research fields and preliminary results may be promising. In conclusion, such findings, if confirmed through future research, should represent evidence for the efficacy of dietary supplementation as a support to standard pharmacological and psychological therapies in children and adolescents with ADHD.

Polyunsaturated fatty acids (PUFAs) biostatus has been proposed as possible attention deficit hyperactivity disorder (ADHD) diagnosis biomarker. The present exploratory study aimed to investigate the association between PUFAs biostatus and cerebral cortex metabolism measured by functional Near Infrared Spectroscopy (fNIRS) in a sample of children with and without ADHD. 24 children with ADHD and 22 typically developing (TD) peers, aged 8–14, were recruited. Linoleic, arachidonic, docosahexaenoic and eicosapentaenoic acids levels were evaluated in whole blood. All children underwent fNIRS while performing an n-back working memory task. Between groups comparisons revealed lower levels of arachidonic acid in children with ADHD and stronger NIRS signal in TD participants, especially when completing more difficult tasks. Correlations conducted between fNIRS activation and PUFA biostatus revealed several associations between hemodynamic changes in the frontoparietal regions and fatty acids profile across participants. This result was also confirmed by the multiple hierarchical regression analyses that remarked an inverse effect of eicosapentaenoic acid levels on oxyhemoglobin values in right frontoparietal region. Such preliminary findings, if confirmed, would suggest that PUFAs could play a role in atypical neurodevelopment.